Breast cancer is among the most common forms of cancer with over 180,000 new cases diagnosed In the USA each year. Approximately half of all breast cancer patients die from the disease because metastatic breast cancer remains a generally incurable and fatal disease. Cytotoxic drug treatment is an important weapon against cancer. However, cancerous cells frequently develop drug resistance to these agents. We have determined that activation of the Ras/Raf/MEWERK signal transduction cascade will lead to an increased ability of MCF-7 breast cancer cells to proliferate in the presence of the chemotherapeutic drugs doxorubicin and paclitaxel. Consequences of Raf activation may include increased expression of the drug transporter mdr-1, the anti-apoptoticbcl-2 gene, and autocrine growth factors such as such as amphiregulin which bind the HER2 growth factor receptor implicated in the etiology of breast cancer. In the proposed studies, we will determine whether induction of mdr-1, bcl-2and autocrine growth factor expression by theRas/Raf/MEWERK signal transduction pathway is essential for induction of breast cancer drugResistance and the mechanisms by which this occurs. To achieve these objectives, three specific aims have been proposed: Aim 1. To determine mechanisms by which the Ras/Raf/MEWERK pathway regulates mdr-1, bcl-2, and autocrine growth factors and whether their induced expression is required for breast cancer drug resistance ,Aim 2. To determine mechanisms by which the Ras/Raf/MEWERK and Ras/PI3K/PTEN/PDK/Akt pathways interact and regulate mdr-1, bcl-2 and Breast cancer drug resistance. Aim 3. To determine mechanisms by which Ras/Raf/MEWERK Pathway influences the redox status of breast cancer cells to modulate their sensitivity to Chemotherapeutic drugs. Through these studies, more information will be available to treat breast and other cancer patients with combinations of drugs, which inhibit signal transduction and anti-apoptotic pathways leading to drug resistance.